Clinical interventions in central nervous system (CNS) disease management base decisions on primarily deductions from a variety of secondary information and on the individual or collective experience of clinicians rather than direct measurements of brain function, and in particular cerebral blood flow (CBF). A non-invasive, continuous, bed-side instrument for measurement of CBF in the micro-vasculature would, in fact, be highly desirable for management of a variety of CNS disorders such as stroke, hemorrhage, and head trauma. Diagnostics in current use have limitations. For example, available modalities deliver either insufficient information (e.g. transcranial Doppler Ultrasound measurement of velocity within selected arteries) or are relatively inaccessible (Xenon inhalation CT, arterial spin labeling MRI, PET). The premise of this proposal is that a newly developed optical technique can be used to measure absolute CBF. Diffuse correlation spectroscopy (DCS) offers new, non-invasive medical diagnostic tools whose capabilities for relative measurements have recently been demonstrated in functional activation studies of intact human brain. Further developments in DCS are expected to have a clinical impact. To that end, this proposal addresses the shortcomings of DCS in a systematic way. Questions such as; ``What is the biological origin of the signal?'', ``Which tissue volume is being probed?'' and ``Can the absolute, cortical CBF be estimated?'' are addressed via computer simulations, experiments on tissue simulating phantoms and via in vivo studies. If successful, pilot clinical trials and further development of the instrumentation will follow. We expect that in a short time period, the clinical utility of this technology will be established. Another side-benefit of this project will be that other clinical applications in other diseases and organs will be feasible. Clinical interventions in central nervous system (CNS) disease management base decisions on primarily deductions from a variety of secondary information and experience of clinicians rather than direct measurements of cerebral blood flow (CBF). A non-invasive, continuous, bed-side instrument for measurement of CBF in the micro-vasculature would be highly desirable for management of a variety of CNS disorders such as stroke, hemorrhage, and head trauma. The proposed optical technique will take a big step towards fullfiling this void. [unreadable] [unreadable] [unreadable]